Apoptosis stimulators have emerged as key targets for the control of cancer. This therapeutic class has, however, remained predominantly experimental and of the 100 or so molecules in development as apoptosis agonists, approaching 70% of these remain in preclinical development. The low rate of clinical entry associated with these molecules is related to lack of specificity, low efficacy and/or susceptibility to drug resistance. These issues are being addressed as our understanding of the field evolves, and as a result, the identification and exploitation of new targets remains a considerable focus of attention - indeed the number of pro-apoptotic molecules in preclinical development has risen by about 10-fold since 1995

From a molecular point of view this field has concentrated heavily on the caspases and endogenous inhibitors of apoptosis, predominantly Bcl-2 proteins. Over the past few years a considerable amount of research has been conducted and our view of apoptosis has changed dramatically. Major advances have included the emergence of the IAP ("Inhibitor of Apoptosis Proteins") family (see our recent analysis of this field). This field has grown exponentially since 1995 and continues to do so. Although XIAP and survivin remain the better known members of this family, 8 human IAPs have now been identified. Members of this family represent both key regulators of apoptosis and also highly attractive therapeutic targets for the treatment of cancer as well as conditions associated with inappropriately high levels of apoptosis such as that seen after ischemia.

Researchers from Stanford University have recently identified a novel protein, “apoptotic regulator in the membrane of the endoplasmic reticulum” (ARMER), which they suggest enhances IAP function, perhaps by facilitating IAP binding and inhibition of their caspase substrates, or may function in a manner similar to the IAPs. ARMER is reportedly expressed in all human tissues tested with highest expression in brain, testis, and liver and is an integral membrane protein in the ER. Overexpression in HT1080 cells, a human fibrosarcoma cell line, prevented apoptosis induced by the removal of serum from media, the addition of doxorubicin or UV irradiation.

The three main apoptotic pathways identified thus far (the mitochondrial, endoplasmic reticulum (ER) stress, and death receptor pathways) are activated by caspase-9, -12, and -8, respectively. The mitochondrial pathway may also serve as a point of convergence for the other two pathways, since death receptor activation and ER stress can both lead to cytochrome c release from the mitochondria and subsequent caspase-9 activation. Once cleaved caspase-9 activates caspase-3, the primary executioner caspase although this caspase is also activated independently of the mitochondrial pathway by, for example, caspase-8. Consistent with its localization to the ER, ARMER prevent apoptosis induced by a variety of ER stressors. Although ARMER did not inhibit release of cytochrome c or the cleavage of caspase-9, caspase-3 cleavage was inhibited in ARMER-expressing cells. This was related to a decrease in caspase-9 activity.

These data therefore suggest that ARMER is a key regulator of apoptotic cell death and that its inhibition may confer increased sensitivity to anti-cancer treatments. The potential of ARMER as a therapeutic target is further increased by observations that the gene for ARMER (KIAA0069) is more highly expressed in colon adenocarcinomas than in adenomas or normal colon tissues and is also highly expressed in rapidly proliferating breast tumors. The development and investigation of strategies able to block ARMER is therefore eagerly awaited.

Entry date Tuesday, July 01, 2003

Adapted from Lui et al, Mol Cancer Res. 2003 May;1(7):508-18.

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